Drug resistance to antibiotics, especially beta lactam antibiotics, such as penicillin, cephalosporin and related compounds, is one of the most serious problems in the treatment of infectious diseases. Drug resistance to antibiotics represents not only a significant medical problem, but a major public health and economic burden. Between 1980 and 1992, the death rate, due to infectious diseases as the underlying cause of death, increased 58%, from 41 deaths to 65 deaths per 100,000 people in the United States. Age adjusted mortality from infectious diseases increased 39% during the same period. Infectious disease mortality increased 25% among those aged 65 years and older (from 271 to 338 per 100,000) and 6.3 times among 25-44 year olds (from 6 to 38 per 100,000). Mortality due to respiratory tract infections increased 20% (from 25-30 deaths per 100,000).
Recent CDC reports indicate that two million Americans acquire infections in hospitals each year, the cost of which runs to an estimated $4.5 billion. In 2003, epidemiologists reported in The New England Journal of Medicine that 5 to 10 percent of patients admitted to hospitals acquire an infection during their stay and that the risk for a hospital-acquired infection has increased steadily in recent decades. Of these infections, 70% are due to microbes that are resistant to one or more antibiotics and in 30-40% of the infections the causative microbe is resistant to first line treatment. The rate at which patients acquire infections in hospitals rose by 36% in 1995 compared with 1975. In 1995, 35.9 million patients entered hospitals in the United States compared with 37.7 million in 1975. For the same period, lengths of stay dropped to an average of 5.3 days from 7.9 days due to managed health care guidelines. The number of infections per 1,000 patient days, however, rose to 9.77 from 7.18.
Penicillin exerts its effects by disrupting the synthesis of the bacterial cell wall. The endogenous bacterial enzymes that destroy penicillin and other beta lactam antibiotics and eliminate their efficacy are the beta lactamases. The name derives from their ability to cleave the beta lactam ring of the antibiotic. At the clinical level, the most important beta lactamases belong to the so-called class A enzymes (TEM) and to the class C enzymes (AmpC). These enzymes are serine hydrolases; they have a critical serine in their catalytic site. The metallo-enzyme Class B beta-lactamases (IMP) also are important clinically. To overcome the negative effects of these enzymes, small molecules that neutralize the action of beta lactamase (beta lactamase inhibitors) are commonly used in combination with antibiotics. The three beta lactamase inhibitors currently in clinical use, clavulanic acid, sulbactam and tazobactam, are all transition state analogs that utilize the same beta lactam core that is present in the antibiotics themselves.
A disturbing trend has been the growing number of bacteria that have evolved resistance mechanisms against beta lactamase inhibitors. A major form of resistance is the appearance of mutations in the beta lactamase enzymes that abolish the effectiveness of the inhibitors while preserving the ability of the enzymes to hydrolyze the antibiotic molecules. These observations underscore the need for new non-beta lactam based beta lactamase inhibitors that are active against a wide variety of beta lactamases, including those that are resistant to clavulanic acid, sulbactam and tazobactam.